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MS Academia: Multiple sclerosis advanced course

6 October 2015 - Barcelona, Spain

2

DECLARATION DISCLOSURE

Letizia Leocani:

Advisory board: Abbvie, Novartis, Biogen

Travel support: Novartis, Genzyme, Merck Serono, Almirall

Research support: Merck Serono, Almirall

Speakers bureau: Serono Symposia International

Foundation; Excemed

Faculty disclosure

Neurophysiology in diagnosis and monitoring of MS Letizia Leocani Experimental Neurophysiology Unit and MAGnetic IntraCerebral Stimulation-MAGICS Center INSPE-Institute of Experimental Neurology Hospital San Raffaele, Milan, Italy

MS Academia

Barcelona, Oct 6, 2015

MS functional deficits: pathological substrates

A

B

N1 N2

Demyel.N1 N2

Conduction block in demyelinated fiber

Courtesy of Dr. J. Black

Segmental demyelination: conduction slowing (block if >5mm; McDonald& Sears 1979)

5mm

Inflammation(+Demyelination) axonal conduction block

Axonal/neuronal degeneration acute, delayed, transynaptic

Trapp et al. 1999

Redford et al. 1997

Smith et al 2001

Low sodium channel density in the demyelinated axon membrane contributes to conduction failure, with the negative signs and symptoms

Evoked Potentials “Expanded Neuro(physio)logical Examination”

• Somatosensory-SEP, Motor-MEP

• brain - spinal cord

• Visual-VEP

• optic nerve

• Auditory-BAEP

• brainstem

• Cognitive-Event-related Potentials

• brain

EPs abnormalities

•Delayed latency

•Demyelination

•most often asymptomatic (if without conduction block)

•detection of subclinical lesions

•may be predictive of future axonal loss

•Reduced amplitude

•Transient: conduction block (demyelination/inflammation)

•Permanent: axonal loss

•Corresponds with clinical impairment but difficult to demonstrate because of high variability (synaptic activity!!)

EPs for measuring axonal damage - Limits

Problems in interpreting standard EPs amplitude measures

Amplitude results from a combination of axons/neurons available for conduction, synaptic efficiency, neuronal excitability

-Highly influenced by:

•Axonal/neuronal loss (irreversible)

•Mediators of inflammation (reversible)

•Synaptic activity (reversible)

plus equipment, electrode/source distance (skull thickness, atrophy…)

Variability between individuals, labs, time from event

8

Optic nerve assessment techniques - VEPs

Visual evoked potentials (VEP)

Latency (ms)

Am

plit

ude

(µ

m)

Full-field VEP Multifocal VEP

Visual EPs in MS

1- Normal

2- Amplitude asymmetry

3- Latency delay

4- Amplitude asymmetry & latency delay

Anderson et al 1987

1

2

3

4

normal

Smith et al 1986

basal

1 week

1 month

Acute Optic Neuritis after high-dose steroids Reversible conduction block: rapid amplitude recovery

VEPs

Somatosensory evoked potentials

C3 C4

Fpz

Erb

Extra

Glott

Cv7

GND

Somatosensory EPs – abnormalities

from Anderson et al 1987 - modified

3

Normal > N20 latency

N13 absent N13 and N20 absent

Progression no longer detectable!

Supra-threshold depolarization of corticospinal neurons

Transcranial Magnetic Stimulation - TMS

Di Lazzaro et al. 2012

Spinal cord

EMG-MEP

Spinal cord

Stim. 1

Stim. 2

Reg.

Ref.

GND

5 msec /div

TCMC = TCMT - TCMP

mV

TCMP TCMT

t

B

70 sec

max 2.1 T

Stim. 1

Stim. 2

Motor Evoked Potentials - MEPs

A.B. , female, 27 yrs Multiple Sclerosis relapse upper limbs MEPs July 29th 03

right left Acute paresis (1st week)

Recovery (1 month follow-up) Sept 1, 03

Thickbroom et al 2005

Correlation between Motor central conduction time and hand dexterity

**

MS - Frequency of EPs abnormalities (%) n. 116: 50 RR, 48 SP, 18 PP

°

PP vs RR: ° p<0.02

SP vs RR: * p<0.02; ** p<0.001

* * *

Leocani et al, JNNP 2006

115 CIS patients (all with > MRI lesions) followed for 5 years

abnormal VEPs in 47.0% • symptomatic: 83% • asymptomatic: 34.1% abnormal MEPs in 50.6% • symptomatic: 58.5% • asymptomatic: 35.7%

Di Maggio et al. in prep.

VEPs

(115)

BAEPs (109)

SEPs (114)

MEP (93)

Total EP abnormalities 47% 17.5% 67.5% 50.6%

Sensitivity (symptomatic) 83.3% 27.0% 67.7% 58.5%

Sensitivity (asymptomatic) 34.1% 12.5% 67.3% 35.7%

Low EPs sensitivity in CIS even if MRI+

Asymptomatic MEP abnormalities (N=31) predicted CDMS (p=0.008): sensitivity 52.7%, specificity 86.7%, NPV 33.3%, PPV 93.5%, Odds Ratio 7.25 No association: VEPs (p=0.77. N=67) SEPs (p=1.0, N=42) BAEPs (p=0.45, N= 68)

EPs and conversion to CDMS over 2 years 115 CIS with >2 brain MRI lesions

Pro

po

rtio

n o

f d

isea

se-f

ree

pts

months

Di Maggio et al. in prep

n: 115 (MRI+)

EPs<4

EPs<4

Eps>4

Eps>4

MR

I > 9

M

RI <

9

Subclinical MEPs involvement in CIS predicts future motor FS involvement (5 yrs)

• VEPs: PPV=15.8% • BAEPs: PPV=55.6% • SEPs: PPV=38.8% • MEPs: PPV=90.0% (p=0.03)

Di Maggio et al. in prep.

115 CIS with >2 brain MRI lesions

Motor evoked potentials may predict EDSS (2 yrs) in RRMS with 80% accuracy (80 RRMS)

6 yrs disease duration, basal EDSS 2

Bejerano et al 2011

PPMS: EPs score VEPs+MEPs prediction of EDSS at 3 yrs

22 PPMS patients followed for 3 years (mean disease duration 5 yrs)

Schlaeger et al MSJ 2013

Zeller et al 2014

Jung et al 2008

worsened

stable

Longitudinal MEPs changes (2 yrs)

Central Motor Conduction Time

EDSS MRC (strength)

1 g/day

2 g/day

Fierro et al 2002

MEPs changes after 5 days of steroids (24 pts)

Motor Threshold intensity

Retina: accessible CNS extension • Similarities: anatomy, function, response to insult, immunology

• Major neurodegenerative disorders reflected in the retina • Technical advances in ocular imaging / function • Convenient platform to study CNS diseases and therapies

+ P100

We have the tools to monitor in vivo

neurodegeneration

Retrograde Anterograde Transynaptic

Petzold 2015

Human optic nerve vs corticospinal tract

Number of axons in the optic nerve

• 800,000-1 million (Polyak, 1941)

• 564,776-1,140,030 (Bruesch and Arey, 1942)

• 1,200,000 (Quigley et al., 1982; Balaszi et al., 1984)

Number of cones to ganglion cells in the fovea

• 1 cone to 2 ganglion cells out to about 2.2o (Schein, 1988)

Number of corticospinal axons in the pyramids

• 1 million (700,000 myelinated)(Lassek 1940, Lassek&Evans 1945)

• Myelination starts at the internal capsule and peduncles in the 10-14 day in the neonate and completes in the second year after birth, along with the acquisition of motor skills

…. Examination of the retinal nerve fibre layer at the optic disc revealed that more than 50% of neural tissue must be lost before a visual defect is clinically evident

Quigley and Addicks 1982

CNS redundancy

Jenkins et al, Ann Neurol 2010;67:99–113

Neuroplasticity Predicts Outcome of Optic Neuritis Independent of Tissue Damage

Clinical/Instrumental paradox – 2

Primary outcome: contrast sensitivity -Arden plates- after 6 months of treatment (64 pts)

10 pts

VEPs latency Visual acuity

better

worse better

worse

Connick et al 2012

clinical evidence of optic involvement (ON history, Uhthoff or optic atrophy Abnormal VEPs consistent with demyelination + optic nerve T2 lesion RNFL > 45 45 μm in one eye

6 months

Change* in mfVEP latency (substudy) vs. FF-VEP latency (primary

endpoint) at Week 24 in the affected eye compared with the unaffected fellow eye at Baseline

(by ANCOVA)

Gordon Lipkin 2007

Brain atrophy and RNFL thickness

VEP latency correlates with OCT Demyelination associated with RNFL axonal loss

r=-0.64; p<0.001

Di Maggio et al, MS J, 2014

Abnormal tests (%) in eyes with acute ON (<3 months), chronic ON and without ON

0

20

40

60

80

100

AON CON non ON

OCT

VEP

OCT + VEP

McNemar Test

Acute ON (AON) OCT 38.9% VEP 77.3%; p= 0.02 Chronic ON (CON) OCT 68.5% VEP 81.5%; P=0.124 non ON OCT 19.9% VEP 31.7%; p=0.005

Di Maggio et al, in prep

Jenkins et al 2010

better

better better

28 acute ON pts (12 mo followup in 25)

Jenkins et al, Ann Neurol 2010;67:99–113

After acute ON: improved vision & VEPs

Chatziralli et al 2012

After ON: VEP amplitudes improve, RNFL worsens

worse

23 MS pts

RNFL

worse

Kapoor et al - AAN 2015 • Phenitoin (sodium channel blocker) started <15 days from

onset of Optic Neuritis-ON protects axons from neurodegeneration

• 81 pts randomized within 14 days from ON • 39 Ph 4 mg/kg/day

• 42 placebo) 3 mo

• OCT : significant difference vs placebo • protective treatment effect 30% RNFL, 34% macula

• VEPs: n.s.

• Vision recovered well in both groups • No significant difference between treatments

VEPs* delay in the FELLOW eye of ON → reduced RNFL

Klistorner et al Neurology 2013 *multifocal VEPs

40

Acute “clinical ON” VEPs improve

Chronic “neurophysiological ON” VEPs do not improve

Niklas et al 2009

Garcia-Martin 2011

Similar rate of RNFL decline in non ON vs chronic ON

RNFL decline* → EDSS worsening *independent of optic neuritis

no ON during follow-up excluded 16 pts with ON <6 months at baseline (18 eyes: 2 pts had bilateral ON)

75 pts followed for 1.5-2.5 years

Pisa et al ECTRIMS 2015

(25) (26)

n. 29

n. 103

N. 59 pts N. 59 pts (132 eyes)

p < 0.001

Multiple sclerosis Neuromyelitis optica

from Wingerchuk, Lancet Neurol 2007

Oligoclonal bands

VEPs in MS-NMOab+ more frequently absent

Watanabe et al Mult Scler 2009

Mealy et al AAN 2014

Optic neuritis in NMO: longer lesions (as in the spinal cord)

Neto SP, Papais Alvarenga RM, et al.; Multiple Sclerosis 2012

VEPs in NMO 19 pts; average n. of visual attacks 2.5 (chronic)

109 ms

99 ms

Latency normal (or mildly delayed? Asymmetry not considered) Amplitude reduced in …%; absent in …%

MS pattern: delayed latency, preserved amplitude NMO pattern: preserved latency*, reduced amplitude (cutoff 5.8 mV)

*Normal latency compared with upper limits (in this example, asymmetry ~10 ms)

73%

27% 35%

65%

143

129

ms

Straffi et al in prep

VEPs after ON in NMO spectrum disorder (19) and MS (18) pts

Study design

• Observational, cross-sectional study

50 NMOSD patients 57 MS patients 68 healthy controls

(HC)

with comparable age

and gender distribution

Full-field VEP

Multifocal VEP

RNFL scans

Macular scans

OCT

High- and low-contrast

visual acuity test

Clinical evaluation

Binocular optic nerve integrated structural-functional evaluation

Differentiate

NMOSD from MS

in ON+ eyes

Better characterize

subclinical damage

in NMOSD eyes

Highlight in vivo differences

in pathophysiology

3 objectives

① ② ③

56 eyes with

previous ON

44 eyes

without ON

55 eyes with

previous ON

59 eyes

without ON

48 Distribution of peripapillary RNFL thickness. Generalized estimating equation (GEE) model with diagnostic group as regressor

(chi-squared test, p < 0.001 overall) and post-hoc comparisons. Significance: [*] = p < 0.05, [**] = p < 0.01, [***] = p < 0.001.

60 µm threshold MS

N

MO

SD

Differentiate NMOSD and MS in ON+ eyes

RNFL lower in NMOSD than MS

Distribution of full-field VEP latency. GEE model with diagnostic group as regressor

(chi-squared test, p < 0.001 overall) and post-hoc comparisons.

Differentiate NMOSD and MS in ON+ eyes

VEP latency higher in MS than in NMOSD

• Differently from MS, latency in NMOSD is rarely delayed over 150 ms

Proportion of eyes with alteration of full-field VEP

latency according to 150 ms threshold. Chi-squared

test between MS and NMOSD, p = 0.006.

150 ms threshold MS

N

MO

SD

/MS

Sensitivity for MS: 14% (95% CI: 7-26%)

Specificity for MS: 98.2% (95% CI: 89.0-99.9%)

Latency

> 150 ms

VEPs in differential diagnosis of MS vs NMO: what we learned from our experience

• In eyes with history of optic neuritis, OCT RNFL scans with 60 µm threshold best differentiate NMOSD (< 60 µm in 88%) from MS (≥ 60 µm in 93%).

• Full-field VEP latency delayed over 150 ms points to MS instead of NMOSD, independently from optic neuritis status.

• In eyes without optic neuritis, subclinical alterations at either OCT or full-field VEP are found with similar overall frequency (53-61%).

• However, combined VEP and OCT alterations are more typical of MS (20%) compared to NMOSD (3%).

51

NMOSD (38/57 eyes with P100): latency increase 0.03±0.10 ms for 1 µm RNFL loss MS (100/104 with P100): latency increase 0.50±0.15 ms for 1 µm RNFL loss

Vabanesi et al, unpublished

52

NMOSD Axonal loss

NMO vs MS: Different pathophysiological patterns reflected by the balance between demyelination and axonal damage

• Axonal damage predominates over demyelination

• Full-field VEP absent in 83% eyes under 60 µm RNFL (mfVEP suggested)

• Severe atrophy due to overt, rather than subclinical, optic neuritis events

MS Demyelination

• Demyelination predominates over axonal loss

• VEP rarely absent, latency delay can be over 150 ms

• Demyelination and axonal loss also due to subclinical events (36%)

Multifocal VEPs – higher sensitivity?

Woman, 68 year old - blurred vision in Left eye (inferior visual field) left fronto-basal meningioma

ffVEPs

119 msec, Amp 14,7 µV 119 msec, Amp 10 µV

Automated Perimetry Automated Perimetry OD OS

mfVEP amplitude asymmetry

OCT mfVEP

OD OS

Amplitude reduction (14-85%)

0.4 µV

OCT

OCT:

VEPs Right: normal VEPs Left: absent

Normal ↑ RNFL = edema (mild)

Woman, 19 year old (E.L)

ON left eye 7 days before (Emergency dep.t)

March 7, 2013

116 msec

VEPs Right (“unaffected”): mild latency Left (ON): improvement - increase 126 msec marked delay 160 msec

160 msec 126 msec 3 days before: 116msec!!!

March 13, 2013

Right: No VEP or visual improvement Left: VEP improvement (133 msec)

VEPs Right: absent

133

VEPs Left: better

April 10, 2013

Right: RNFL loss starts to be evident

Left: normal

VEPs Right: absent

120

VEPs Left: ~normal

Right: mild visual improvement (VEPs still absent )

Left: further VEP improvement (120 msec, upper limit)

May 5, 2013

October 2013 (mfVEPs)

NMO MBV, 60 yrs, episodes of ON in both eyes

Absolute latency map

AL – 16 yrs, female

• Female, 16 yrs, brainstem dysfunction in August and December 2010.

• Brain MRI: T2 hyperintense lesions in brainstem, along the third ventricle, right insula and left thalamus

• Oligoclonal bands absent. Anti-aquaporin antibodies negative.

• Clinical/radiological abnormalietis recovered after intravenous steroids

• 3 episodes of optic neuritis (ON): October 2010 (R), April 2011 (L) and October 2011 (R) – every time recovery with steroids.

• Diagnosis of MS: start glatiramer acetate in November 2011

• She did well until September 2013: left ON with recovery

AL, 16 yrs, female

Global RNFL 71um vs 87um 5 months before

5 months after the last left ON (March 2014)

Full field VEP improved but delayed, RNFL reduced, asymmetry of multifocal VEP amplitudes (worse in left eye)

Right eye

Left eye

AL, 16 yrs, female

Global RNFL 71um vs 87um 5 months before

5 months after the last left ON (March 2014)

VEP improvement, RNFL worsening, asymmetry of multifocal VEP amplitudes (worse in OS)

Right eye

Left eye

ANTI-MOG +

INSPE - Institute of Experimental Neurology, San Raffaele, Milan Director: Prof Giancarlo Comi

Exp. Neurophysiology Unit – MAGICS Center Neurorehabilitation

Raffaella Chieffo Giovanni Di Maggio Laura Ferrari Mario Fichera Simone Guerrieri Elise Houdayer Arturo Nuara Roberto Santangelo Francesco Vitali

Mauro Comola Filippo Martinelli Boneschi Antonella Poggi Federica Esposito Filippo Martinelli-Boneschi

MS center Vittorio Martinelli Lucia Moiola Mariaemma Rodegher Bruno Colombo

NeuroImmunology

G. Martino R. Furlan M. Bacigaluppi & Co